Sex Differences in Antiretroviral Therapy Initiation in Pediatric HIV Infection

The incidence and severity of infections in childhood is typically greater in males. The basis for these observed sex differences is not well understood, and potentially may facilitate novel approaches to reducing disease from a range of conditions. We here investigated sex differences in HIV-infected children in relation to antiretroviral therapy (ART) initiation and post-treatment outcome. In a South African cohort of 2,101 HIV-infected children, we observed that absolute CD4+ count and CD4% were significantly higher in ART-naïve female, compared to age-matched male, HIV-infected children. Absolute CD4 count and CD4% were also significantly higher in HIV-uninfected female versus male neonates. We next showed that significantly more male than female children were initiated on ART (47% female); and children not meeting criteria to start ART by >5yrs were more frequently female (59%; p<0.001). Among ART-treated children, immune reconstitution of CD4 T-cells was more rapid and more complete in female children, even after adjustment for pre-ART absolute CD4 count or CD4% (p=0.011, p=0.030, respectively). However, while ART was initiated as a result of meeting CD4 criteria less often in females (45%), ART initiation as a result of clinical disease in children whose CD4 counts were above treatment thresholds occurred more often in females (57%, p<0.001). The main sex difference in morbidity observed in children initiating ART above CD4 thresholds, above that of TB disease, was as a result of wasting and stunting observed in females with above-threshold CD4 counts (p=0.002). These findings suggest the possibility that optimal treatment of HIV-infected children might incorporate differential CD4 treatment thresholds for ART initiation according to sex

Hepatitis B virus (HBV): serological markers of infection and immunity in a cohort of South African children

Children age 6-60 months were recruited as part of the Co-infection in South-African Children (COSAC) study, in Kimberley, South Africa. HIV-negative participants (n=174) were recruited through the Kimberley Respiratory Cohort (KReC). These children were admitted to hospital with a clinical diagnosis of respiratory tract infection between July 2014 and August 2016. HIV-positive children (n=136) were recruited primarily from HIV outpatient clinics, (recruited between September 2009 and July 2016). Children had research blood samples taken at the same time as routine clinical blood tests. We tested all samples for markers of hepatitis B virus (HBV) infection and immunity. HBsAg testing was carried out in Kimberley Hospital, South Africa using the Magnetic parcel chemiluminometric immunoassay (MPCI; Advia Centaur platform). Confirmatory HBsAg testing, together with anti-HBs and anti-HBc testing, was carried out by the microbiology department at Oxford University Hospitals (OUH) NHS Foundation Trust, Oxford, UK (Architect i2000). Ethics approval for this study was obtained from the Ethics Committee of the Faculty of Health Science, University of the Free State, Bloemfontein, South Africa (HIV Study Ref: ETOVS Nr 08/09 and COSAC Study Ref: ECUFS NR 80/2014). Written consent for enrollment into the study was obtained from the child’s parent or guardian

HBV vaccination and PMTCT as elimination tools in the presence of HIV: insights from a clinical cohort and dynamic model

Abstract Background Sustainable Development Goals set a challenge for the elimination of hepatitis B virus (HBV) infection as a public health concern by the year 2030. Deployment of a robust prophylactic vaccine and enhanced interventions for prevention of mother to child transmission (PMTCT) are cornerstones of elimination strategy. However, in light of the estimated global burden of 290 million cases, enhanced efforts are required to underpin optimisation of public health strategy. Robust analysis of population epidemiology is particularly crucial for populations in Africa made vulnerable by HIV co-infection, poverty, stigma and poor access to prevention, diagnosis and treatment. Methods We here set out to evaluate the current and future role of HBV vaccination and PMTCT as tools for elimination. We first investigated the current impact of paediatric vaccination in a cohort of children with and without HIV infection in Kimberley, South Africa. Second, we used these data to inform a new parsimonious model to simulate the ongoing impact of preventive interventions. By applying these two approaches in parallel, we are able to determine both the current impact of interventions, and the future projected outcome of ongoing preventive strategies over time. Results Existing efforts have been successful in reducing paediatric prevalence of HBV infection in this setting to < 1%, demonstrating the success of the existing vaccine campaign. Our model predicts that, if consistently deployed, combination efforts of vaccination and PMTCT can significantly reduce population prevalence (HBsAg) by 2030, such that a major public health impact is possible even without achieving elimination. However, the prevalence of HBV e-antigen (HBeAg)-positive carriers will decline more slowly, representing a persistent population reservoir. We show that HIV co-infection significantly reduces titres of vaccine-mediated antibody, but has a relatively minor role in influencing the projected time to elimination. Our model can also be applied to other settings in order to predict impact and time to elimination based on specific interventions. Conclusions Through extensive deployment of preventive strategies for HBV, significant positive public health impact is possible, although time to HBV elimination as a public health concern is likely to be substantially longer than that proposed by current goals

Indications for ART Initiation in 222 children whose CD4 counts were above CD4 treatment thresholds.

<p>^a Not within the guidelines for ART initiation in children</p><p>Indications for ART Initiation in 222 children whose CD4 counts were above CD4 treatment thresholds.</p

Strong sex bias in elite control of paediatric HIV infection

Reports of posttreatment control following antiretroviral therapy (ART) have prompted the question of how common immune control of HIV infection is in the absence of ART. In contrast to adult infection, where elite controllers have been very well characterized and constitute approximately 0.5% of infections, very few data exist to address this question in paediatric infection.Methods:We describe 11 ART-naive elite controllers from 10 cohorts of HIV-infected children being followed in South Africa, Brazil, Thailand, and Europe.Results:All but one of the elite controllers (91%) are females. The median age at which control of viraemia was achieved was 6.5 years. Five of these 11 (46%) children lost control of viraemia at a median age of 12.9 years. Children who maintained control of viraemia had significantly higher absolute CD4 cell counts in the period of elite control than those who lost viraemic control. On the basis of data available from these cohorts, the prevalence of elite controllers in paediatric infection is estimated to be 5-10-fold lower than in adults.Conclusion:Although conclusions are limited by the study design, these data suggest that, whilst paediatric elite control can be achieved, compared with adult elite controllers, this occurs rarely, and takes some years after infection to achieve. Also, loss of immune control arises in a high proportion of children and often relatively rapidly. These findings are consistent with the more potent antiviral immune responses observed in adults and in females

Sex differences in CD4+ T cell count, CD4% and viral load, amongst 2,101 ART-naïve South African children.

<p>A. Absolute CD4 counts changes with age. B. CD4% changes with age. C. Viral load changes with age. In each panel, the solid lines are Loess-smoothed regression lines for female children and the dotted lines are Loess-smoothed regression lines for male children. A multivariable linear regression model, with both sex and age as covariates, shows significantly lower absolute CD4 counts in males (p = 0.005); significantly lower CD4% in males (p = 3.7x10^-7); and no significant difference in viral load between the sexes.</p

Proportion of HIV-infected children who were female in the subgroups analyzed within the Kimberley cohort.

<p>The proportion of female children in whom ART was initiated at CD4 counts higher than the CD4 thresholds compared to those in whom ART was initiated at CD4 counts lower than the CD4 thresholds differed significantly (p<0.001).</p

Study cohorts of HIV-infected South African children analyzed.

<p>Study cohorts of HIV-infected South African children analyzed.</p

Absolute CD4 count, CD4% and viral load in HIV-infected children and HIV-uninfected neonates.

<p>^<b>a</b> Mann Whitney test</p><p><u>HIV-Infected Children, n = 2,101</u>.</p